Alpha-2-delta ligands may be defined as compounds which selectively displace 3H-gabapentin from porcine brain membranes indicating a high affinity interaction with the alpha-2-delta (α2δ) subunit of voltage-gated calcium channels. Alpha-2-delta ligands also includes compounds which do not displace 3H-gabapentin, but are structurally similar to compounds that do, which might be expected to bind alpha-2-delta at a slightly different site than 3H-gabapentin or may bind to human brain alpha-2-delta but not porcine alpha-2-delta. They may also be known as GABA analogs.
Alpha-2-delta ligands have been described for a number of indications. The best known alpha-2-delta ligand, gabapentin (NEURONTIN®), 1-(aminomethyl)-cyclohexylacetic acid, was first described in the patent literature in the patent family comprising U.S. Pat. No. 4,024,175. The compound is approved for the treatment of epilepsy and neuropathic pain.
A second alpha-2-delta ligand, pregabalin, (S)-(+)-4-amino-3-(2-methylpropyl)butanoic acid, is described in European patent application publication number EP641330 as an anti-convulsant treatment useful in the treatment of epilepsy and in EP0934061 for the treatment of pain.
Further WO0128978, describes a series of alpha-2-delta ligands, particularly (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, depicted below:

More recently, International Patent Application Number PCT/IB02/01146 (unpublished at the priority date of the present invention) and published as WO02/085839, describes a series of alpha-2-delta ligands of the following formulae:

wherein R1 and R2 are each independently selected from H, straight or branched alkyl of 1-6 carbon atoms, cycloalkyl of from 3-6 carbon atoms, phenyl and benzyl, subject to the proviso that, except in the case of a tricyclooctane compound of formula (XVII), R1 and R2 are not simultaneously hydrogen; for use in the treatment of a number of indications, including pain.
International Patent application No. PCT/IB03/00976, unpublished at the filing date of the present invention, describes compounds of the formula I, below:

wherein R1 is hydrogen or (C1-C6)alkyl optionally substituted with from one to five fluorine atoms;
R2 is hydrogen or (C1-C6)alkyl optionally substituted with from one to five fluorine atoms; or
R1 and R2, together with the carbon to which they are attached, form a three to six membered cycloalkyl ring;
R3 is (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C3)alkyl, phenyl, phenyl-(C1-C3)alkyl, pyridyl, pyridyl-(C1-C3)alkyl, phenyl-N(H)—, or pyridyl-N(H)—, wherein each of the foregoing alkyl moieties can be optionally substituted with from one to five fluorine atoms, preferably with from zero to three fluorine atoms, and wherein said phenyl and said pyridyl and the phenyl and pyridyl moieties of said phenyl-(C1-C3)alkyl and said pyridyl-(C1-C3)alkyl, respectively, can be optionally substituted with from one to three substituents, preferably with from zero to two substituents, independently selected from chloro, fluoro, amino, nitro, cyano, (C1-C3)alkylamino, (C1-C3)alkyl optionally substituted with from one to three fluorine atoms and (C1-C3)alkoxy optionally substituted with from one to three fluorine atoms;
R4 is hydrogen or (C1-C6)alkyl optionally substituted with from one to five fluorine atoms;
R5 is hydrogen or (C1-C6)alkyl optionally substituted with from one to five fluorine atoms; and
R6 is hydrogen or (C1-C6)alkyl;
and the pharmaceutically acceptable salts of such compounds.
Inhibitors of the cyclic guanosine 3′,5′-monophosphate phosphodiesterase type five (cGMP PDEV) enzyme (‘PDEV inhibitors’) may be characterized by compounds with high affinity and selectivity for the PDEV enzyme with little or no affinity for the other phosphodiesterase isoforms and they have been described as being useful for treating a number of indications. In particular, sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one) (VIAGRA®) has been described for the treatment of a number of cardiovascular disorders and has proved to be successful as the first orally effective treatment for male erectile dysfunction (MED). The use of PDEV inhibitors in the treatment of neuropathy has been described in European Patent Application Number EP1129706 and WO01/26659. Analgesic effects of sildenafil have recently been described in Jain et al, Brain Research, 909, 170-178 (2001); Asomoza-Espinosa et al, Eur. J. Pharm., 418, 195-200 (2001); and Mixcoatl-Zecutal et al, Eur. J. Pharm., 400, 81-87 (2001).